The long-term goal of this project is to identify functions of RGS proteins and the mechanisms that regulate them. The focus of the present application is RGS2, which has been linked genetically in mice and humans to hypertension. The central hypothesis is that RGS2 regulates blood pressure by carrying out discrete functions in vascular smooth muscle, vascular endothelium, and kidney. This project focuses on the ability of RGS2 to regulate vascular contraction and relaxation by functioning in vascular smooth muscle, endothelium and to regulate fluid transport in renal nephron. It uses cell type- specific RGS2 knockout mice in conjunction with biochemical, cell biological, physiological and imaging methods to address the following Specific Aims: 1) determine how RGS2 degradation is regulated in vascular smooth muscle;2) determine the relative contributions of RGS2 in vascular smooth muscle, endothelium and nephron in blood pressure control;3) determine how RGS2 promotes endothelium-dependent vascular relaxation;and 4) determine whether RGS2 regulates the ability of vasoconstrictors to regulate RhoA signaling ex vivo and in vivo. Accordingly, this project advances understanding of blood pressure control mechanisms and their dysregulation in hypertension, which may contribute to the identification of new hypertension therapies. PUBLIC HEALTH RELEVANCE: Hypertension affects 50 million Americans, making this condition a leading mortality risk factor due to its association with greatly increased risk of cardiovascular disease, renal failure, diabetes and stroke. Hypertension causes enormous clinical and societal burden because ~70% of the patient population is poorly treated by currently available therapeutics. Improved treatment is likely to occur when therapeutics can be tailored to a patient's genetics. This project advances this goal by determining how a newly identified hypertension-linked gene---RGS2-regulates blood pressure.